Fibrillar deposits of proteinaceous material (“amyloid”) accompany a plethora of diseases. So-called amyloid diseases such as Alzheimer's disease, bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease (CJD), laughing death syndrome, and scrapie are all neurodegenerative diseases characterized pathologically by the presence of extracellular amyloid deposits or plaques in brain tissue. So far, at least 23 unrelated proteins are known to either form an insoluble structure known as a β-sheet or to be precursors of peptides that form into β-sheets. These proteins (sometimes referred to herein as “fibrillizing peptides”) tend to aggregate into fibrils and then into more complex insoluble deposits associated with diseases, collectively referred to as amyloidoses (Baethge et al., eMedicine.com, 2006, accessible on the world wide web as med/topic 3377).
For example, Aβ peptides (or “amyloid beta peptides,” “A-beta peptides” or simply “Aβ”) are fibrillizing peptides having 39-43 amino acids. The most common of the wild-types are Aβ-40 and Aβ-42. Aβ-40 is more abundant, but Aβ-42 is more fibrillogenic. They are produced proteolytically from the amyloid β-protein precursor (AβPP), a large, type I integral membrane protein, through sequential proteolysis by β- and γ-secretase activities (Vassar et al., Science 286:735-741, 1999, Beck et al., J. Med. Chem. 46:4625-4630, 2003, DeStrooper et al., Nature 391:387-390, 1998, Wolfe et al., Nature 398:513-517, 1999). Depositions of Aβ in the parenchyma of the brain, which is characteristic of Alzheimer's disease, form readily from soluble molecules, first as soluble oligomers that are toxic in their own right (S. M. Chafekar et al., Biochim. Biophys. Acta 1782:523-31, 2008). It is thought that these oligomers go on to form diffuse plaques which, although insoluble, exhibit little surrounding pathology. However, although not proven, it is widely believed that these diffuse plaques progress to fibrillar forms, thence to fibrillar plaques associated with dystrophic neurons, neurofibrillary tangles, and inflammation (Selkoe, Physiol. Rev. 8:741-766, 2001).
Fibrillar Aβ deposition also occurs within and along primarily small and medium arteries and arterioles of the cerebral cortex and leptomeninges and in the cerebral microvasculature, a condition known as cerebral amyloid angiopathy (“CAA”) (Vinters, Stroke 18: 311-324, 1987, Jellinger, J. Neural Transm. 109:813-836, 2002, Vinters and Farag, Adv. Neurol. 92:105-112, 2003). This condition accounts for up to 20% of all spontaneous primary intracerebral hemorrhages and is a key pathological lesion in nearly all patients with Alzheimer's disease and certain related disorders. Familial CAA stems from mutant forms of Aβ, prominently the Dutch- and Iowa-type mutants. These particular mutant forms of the peptide tend not to accumulate in the brain parenchyma, but they are uncommonly aggressive fibrillizers in vitro and in cerebrovascular tissue compared to wild-type Aβ, all the more so when the peptide carries both mutations at once. Fibrillar forms of the mutants in the cerebral vascular have been shown to cause degeneration and cell death of smooth muscle cells and pericytes in affected larger cerebral vessels and cerebral microvessels, respectively (Vinters and Farag, Adv. Neurol. 92:105-112, 2003, Wisniewski et al., Amyloid 1: 8-16, 1994, Kawai et al., Brain Res. 623:142-146, 1993). Recent findings have implicated cerebral microvascular Aβ deposition in promoting neuro-inflammation and dementia in Alzheimer's disease (Bailey et al., Neurol. Res. 26:573-578, 2004; Attems and Jellinger, Acta Neuropathol. 107:83-90, 2004; Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study, Lancet 357:169-175, 2001; Thal et al., J. Neuropathol. Exp. Neurol. 62:1287-1301, 2003).
Aβ also appears to enhance the accumulation of the alpha-synucleins that comprise the cytoplasmic inclusions found in brain neurons in subjects (mice) with Lewy body dementia (E Masliah, et al., Proc. Natl. Acad. Sci. U.S.A. 98:12245-50, 2001). Baethge et al. (eMedicine.com, 2006, accessible on the world wide web as mod/topic 3377) have assembled a long list of diseases that stem from abnormal accumulations of fibrillizing peptides in cells, tissues and organs of the body. The standard of care for many of the listed maladies is summarized therein. In most cases, care is only palliative. In no case is a treatment curative. The need for more and better ways of preventing the fibrillization of fibrillizing peptides into insoluble deposits is manifest.